Special Issue "The Past, Present and Future of Photodynamic Therapy for Cancers"

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Oncology".

Deadline for manuscript submissions: closed (15 January 2020).

Special Issue Editors

Dr. Sabrina Oliveira
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Guest Editor
Department of Biology and of Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands
Interests: targeted photodynamic therapy; targeted nanomedicines; molecular targeted therapies; molecular imaging, theranostics
Dr. Dominic Robinson
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Guest Editor
Department of Otorhinolaryngology & Head and Neck Surgery, Center for Optical Diagnostics and Therapy, Erasmus Medical Center, Rotterdam, The Netherlands
Interests: photodynamic therapy; dosimetry; optical spectroscopy; image guided surgery; optical diagnosistics; theranostics
Dr. Girgis Obaid
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Guest Editor
Laboratory of Dr. Tayyaba Hasan, Harvard Medical School, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA, USA
Interests: photodynamic therapy; targeted nanomedicines; quantitative molecular imaging; extrinsically-activatable nanotherapeutics; personalized medicine

Special Issue Information

Dear Colleagues,

Photodynamic therapy was introduced more than one hundred years ago as a method that needed three elements to create local toxicity: A light-sensitive chemical, also known as a photosensitizer, light, and oxygen. Since then, many preclinical studies and clinical trials have been conducted showing the great potential of this local cancer therapy, which has also been described to lead to systemic effects through activation of the immune system. Altogether, those studies led to the regulatory approval of PDT as a cancer treatment over thirty years ago. Nonetheless, it is generally accepted that this treatment modality is still underutilized in the clinic. This is for several reasons, among which: a. The complex and variable modes of action of PDT that have yet to be fully exploited in the clinic in order to maximize efficacy; b. the complex dosimetry parameters that can prevent PDT from reaching its fullest potential; and c. the industrial and commercialization challenges faced over these years. Because of these, many aspects are currently being investigated, with the aim of improving the application of PDT in the clinic and rendering it more effective, accessible, and standardized, so that a larger number of cancer patients can benefit from its unique advantages over conventional modalities, such as chemotherapy and radiotherapy.

The present Special Issue aims to address “The Past, Present and Future of PDT” by assembling significant contributions in the following cathegories:

  1. Crucial past efforts made in this field, especially focusing on the work of Dr. Thomas Dougherty, who passed away on October 2nd 2018;
  2. Insights into the present applications of PDT in the clinic;
  3. Current developments focused on improving PDT, such as but not limited to:
    • Macromolecular targeting of photosensitizers;
    • Nanoparticles as photosensitizers’ delivery vehicles;
    • Light delivery and dosimetry;
    • Combination of PDT with other therapies;
    • Immunological component of PDT;
    • Alternatives for hypoxic tumors;
  4. Perspectives on the future of PDT.

We hope this scope will encourage the participation of many researchers and clinicians, who still believe it is possible to render PDT more effective and more commonly available to patients. Contributions can be made in the format of research articles, reviews, communications, perspectives, opinions, concept papers, and case studies.

Dr. Sabrina Oliveira
Dr. Dominic Robinson
Dr. Girgis Obaid
Guest Editors

Manuscript Submission Information

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Keywords

  • Photodynamic therapy
  • Photomedicine
  • Phototherapeutics

Published Papers (19 papers)

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Open AccessArticle
NIR Photodynamic Destruction of PDAC and HNSCC Nodules Using Triple-Receptor-Targeted Photoimmuno-Nanoconjugates: Targeting Heterogeneity in Cancer
J. Clin. Med. 2020, 9(8), 2390; https://doi.org/10.3390/jcm9082390 - 27 Jul 2020
Cited by 3 | Viewed by 948
Abstract
Receptor heterogeneity in cancer is a major limitation of molecular targeting for cancer therapeutics. Single-receptor-targeted treatment exerts selection pressures that result in treatment escape for low-receptor-expressing tumor subpopulations. To overcome this potential for heterogeneity-driven resistance to molecular targeted photodynamic therapy (PDT), we present [...] Read more.
Receptor heterogeneity in cancer is a major limitation of molecular targeting for cancer therapeutics. Single-receptor-targeted treatment exerts selection pressures that result in treatment escape for low-receptor-expressing tumor subpopulations. To overcome this potential for heterogeneity-driven resistance to molecular targeted photodynamic therapy (PDT), we present for the first time a triple-receptor-targeted photoimmuno-nanoconjugate (TR-PIN) platform. TR-PIN functionalization with cetuximab, holo-transferrin, and trastuzumab conferred specificity for epidermal growth factor receptor (EGFR), transferrin receptor (TfR), and human epidermal growth factor receptor 2 (HER-2), respectively. The TR-PINs exhibited up to a 24-fold improvement in cancer cell binding compared with EGFR-specific cetuximab-targeted PINs (Cet-PINs) in low-EGFR-expressing cell lines. Photodestruction using TR-PINs was significantly higher than the monotargeted Cet-PINs in heterocellular 3D in vitro models of heterogeneous pancreatic ductal adenocarcinoma (PDAC; MIA PaCa-2 cells) and heterogeneous head and neck squamous cell carcinoma (HNSCC, SCC9 cells) containing low-EGFR-expressing T47D (high TfR) or SKOV-3 (high HER-2) cells. Through their capacity for multiple tumor target recognition, TR-PINs can serve as a unique and amenable platform for the effective photodynamic eradication of diverse tumor subpopulations in heterogeneous cancers to mitigate escape for more complete and durable treatment responses. Full article
(This article belongs to the Special Issue The Past, Present and Future of Photodynamic Therapy for Cancers)
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Open AccessArticle
Photodynamic Therapy Using a New Folate Receptor-Targeted Photosensitizer on Peritoneal Ovarian Cancer Cells Induces the Release of Extracellular Vesicles with Immunoactivating Properties
J. Clin. Med. 2020, 9(4), 1185; https://doi.org/10.3390/jcm9041185 - 21 Apr 2020
Cited by 3 | Viewed by 773
Abstract
Often discovered at an advanced stage, ovarian cancer progresses to peritoneal carcinoma, which corresponds to the invasion of the serosa by multiple tumor implants. The current treatment is based on the combination of chemotherapy and tumor cytoreduction surgery. Despite the progress and standardization [...] Read more.
Often discovered at an advanced stage, ovarian cancer progresses to peritoneal carcinoma, which corresponds to the invasion of the serosa by multiple tumor implants. The current treatment is based on the combination of chemotherapy and tumor cytoreduction surgery. Despite the progress and standardization of surgical techniques combined with effective chemotherapy, post-treatment recurrences affect more than 60% of women in remission. Photodynamic therapy (PDT) has been particularly indicated for the treatment of superficial lesions on large surfaces and appears to be a relevant candidate for the treatment of microscopic intraperitoneal lesions and non-visible lesions. However, the impact of this therapy on immune cells remains unclear. Hence, the objective of this study is to validate the efficacy of a new photosensitizer [pyropheophorbide a-polyethylene glycol-folic acid (PS)] on human ovarian cancer cells and to assess the impact of the secretome of PDT-treated cells on human peripheral blood mononuclear cells (PBMC). We show that PS, upon illumination, can induce cell death of different ovarian tumor cells. Furthermore, PDT using this new PS seems to favor activation of the immune response by inducing the secretion of effective cytokines and inhibiting the pro-inflammatory and immunosuppressive ones, as well as releasing extracellular vesicles (EVs) prone to activating immune cells. Finally, we show that PDT can activate CD4+ and CD8+ T cells, resulting in a potential immunostimulating process. The results of this pilot study therefore indicate that PS-PDT treatment may not only be effective in rapidly and directly destroying target tumor cells but also promote the activation of an effective immune response; notably, by EVs. These data thus open up good prospects for the treatment of micrometastases of intraperitoneal ovarian carcinosis which are currently inoperable. Full article
(This article belongs to the Special Issue The Past, Present and Future of Photodynamic Therapy for Cancers)
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Open AccessArticle
Flow-induced Shear Stress Confers Resistance to Carboplatin in an Adherent Three-Dimensional Model for Ovarian Cancer: A Role for EGFR-Targeted Photoimmunotherapy Informed by Physical Stress
J. Clin. Med. 2020, 9(4), 924; https://doi.org/10.3390/jcm9040924 - 28 Mar 2020
Cited by 1 | Viewed by 1598
Abstract
A key reason for the persistently grim statistics associated with metastatic ovarian cancer is resistance to conventional agents, including platinum-based chemotherapies. A major source of treatment failure is the high degree of genetic and molecular heterogeneity, which results from significant underlying genomic instability, [...] Read more.
A key reason for the persistently grim statistics associated with metastatic ovarian cancer is resistance to conventional agents, including platinum-based chemotherapies. A major source of treatment failure is the high degree of genetic and molecular heterogeneity, which results from significant underlying genomic instability, as well as stromal and physical cues in the microenvironment. Ovarian cancer commonly disseminates via transcoelomic routes to distant sites, which is associated with the frequent production of malignant ascites, as well as the poorest prognosis. In addition to providing a cell and protein-rich environment for cancer growth and progression, ascitic fluid also confers physical stress on tumors. An understudied area in ovarian cancer research is the impact of fluid shear stress on treatment failure. Here, we investigate the effect of fluid shear stress on response to platinum-based chemotherapy and the modulation of molecular pathways associated with aggressive disease in a perfusion model for adherent 3D ovarian cancer nodules. Resistance to carboplatin is observed under flow with a concomitant increase in the expression and activation of the epidermal growth factor receptor (EGFR) as well as downstream signaling members mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) and extracellular signal-regulated kinase (ERK). The uptake of platinum by the 3D ovarian cancer nodules was significantly higher in flow cultures compared to static cultures. A downregulation of phospho-focal adhesion kinase (p-FAK), vinculin, and phospho-paxillin was observed following carboplatin treatment in both flow and static cultures. Interestingly, low-dose anti-EGFR photoimmunotherapy (PIT), a targeted photochemical modality, was found to be equally effective in ovarian tumors grown under flow and static conditions. These findings highlight the need to further develop PIT-based combinations that target the EGFR, and sensitize ovarian cancers to chemotherapy in the context of flow-induced shear stress. Full article
(This article belongs to the Special Issue The Past, Present and Future of Photodynamic Therapy for Cancers)
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Open AccessArticle
Photodynamic Therapy in Primary Breast Cancer
J. Clin. Med. 2020, 9(2), 483; https://doi.org/10.3390/jcm9020483 - 10 Feb 2020
Cited by 10 | Viewed by 1068
Abstract
Photodynamic therapy (PDT) is a technique for producing localized necrosis with light after prior administration of a photosensitizing agent. This study investigates the nature, safety, and efficacy of PDT for image-guided treatment of primary breast cancer. We performed a phase I/IIa dose escalation [...] Read more.
Photodynamic therapy (PDT) is a technique for producing localized necrosis with light after prior administration of a photosensitizing agent. This study investigates the nature, safety, and efficacy of PDT for image-guided treatment of primary breast cancer. We performed a phase I/IIa dose escalation study in 12 female patients with a new diagnosis of invasive ductal breast cancer and scheduled to undergo mastectomy as a first treatment. The photosensitizer verteporfin (0.4 mg/kg) was administered intravenously followed by exposure to escalating light doses (20, 30, 40, 50 J; 3 patients per dose) delivered via a laser fiber positioned interstitially under ultrasound guidance. MRI (magnetic resonance imaging) scans were performed prior to and 4 days after PDT. Histological examination of the excised tissue was performed. PDT was well tolerated, with no adverse events. PDT effects were detected by MRI in 7 patients and histology in 8 patients, increasing in extent with the delivered light dose, with good correlation between the 2 modalities. Histologically, there were distinctive features of PDT necrosis, in contrast to spontaneous necrosis. Apoptosis was detected in adjacent normal tissue. Median follow-up of 50 months revealed no adverse effects and outcomes no worse than a comparable control population. This study confirms a potential role for PDT in the management of early breast cancer. Full article
(This article belongs to the Special Issue The Past, Present and Future of Photodynamic Therapy for Cancers)
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Open AccessArticle
An Efficient Photodynamic Therapy Treatment for Human Pancreatic Adenocarcinoma
J. Clin. Med. 2020, 9(1), 192; https://doi.org/10.3390/jcm9010192 - 10 Jan 2020
Cited by 5 | Viewed by 1088
Abstract
To date, pancreatic adenocarcinoma (ADKP) is a devastating disease for which the incidence rate is close to the mortality rate. The survival rate has evolved only 2–5% in 45 years, highlighting the failure of current therapies. Otherwise, the use of photodynamic therapy (PDT), [...] Read more.
To date, pancreatic adenocarcinoma (ADKP) is a devastating disease for which the incidence rate is close to the mortality rate. The survival rate has evolved only 2–5% in 45 years, highlighting the failure of current therapies. Otherwise, the use of photodynamic therapy (PDT), based on the use of an adapted photosensitizer (PS) has already proved its worth and has prompted a growing interest in the field of oncology. We have developed a new photosensitizer (PS-FOL/PS2), protected by a recently published patent (WO2019 016397-A1, 24 January 2019). This photosensitizer is associated with an addressing molecule (folic acid) targeting the folate receptor 1 (FOLR1) with a high affinity. Folate binds to FOLR1, in a specific way, expressed in 100% of ADKP or over-expressed in 30% of cases. The first objective of this study is to evaluate the effectiveness of this PS2-PDT in four ADKP cell lines: Capan-1, Capan-2, MiapaCa-2, and Panc-1. For this purpose, we first evaluated the gene and protein expression of FOLR1 on four ADKP cell lines. Subsequently, we evaluated PS2’s efficacy in our cell lines and we assessed the impact of PDT on the secretome of cancer cells and its impact on the immune system. Finally, we evaluate the PDT efficacy on a humanized SCID mouse model of pancreatic cancer. In a very interesting way, we observed a significant increase in the proliferation of activated-human PBMC when cultured with conditioned media of ADKP cancer cells subjected to PDT. Furthermore, to evaluate in vivo the impact of this new PS, we analyzed the tumor growth in a humanized SCID mice model of pancreatic cancer. Four conditions were tested: Untreated, mice (nontreated), mice with PS (PS2), mice subjected to illumination (Light only), and mice subjected to illumination in the presence of PS (PDT). We noticed that the mice subjected to PDT presented a strong decrease in the growth of the tumor over time after illumination. Our investigations have not only suggested that PS2-PDT is an effective therapy in the treatment of PDAC but also that it activates the immune system and could be considered as a real adjuvant for anti-cancer vaccination. Thus, this new study provides new treatment options for patients in a therapeutic impasse and will provide a new arsenal in the fight against PDAC. Full article
(This article belongs to the Special Issue The Past, Present and Future of Photodynamic Therapy for Cancers)
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Open AccessArticle
Immune Responses after Vascular Photodynamic Therapy with Redaporfin
J. Clin. Med. 2020, 9(1), 104; https://doi.org/10.3390/jcm9010104 - 31 Dec 2019
Cited by 4 | Viewed by 1216
Abstract
Photodynamic therapy (PDT) relies on the administration of a photosensitizer (PS) that is activated, after a certain drug-to-light interval (DLI), by the irradiation of the target tumour with light of a specific wavelength absorbed by the PS. Typically, low light doses are insufficient [...] Read more.
Photodynamic therapy (PDT) relies on the administration of a photosensitizer (PS) that is activated, after a certain drug-to-light interval (DLI), by the irradiation of the target tumour with light of a specific wavelength absorbed by the PS. Typically, low light doses are insufficient to eradicate solid tumours and high fluence rates have been described as poorly immunogenic. However, previous work with mice bearing CT26 tumours demonstrated that vascular PDT with redaporfin, using a low light dose delivered at a high fluence rate, not only destroys the primary tumour but also reduces the formation of metastasis, thus suggesting anti-tumour immunity. This work characterizes immune responses triggered by redaporfin-PDT in mice bearing CT26 tumours. Our results demonstrate that vascular-PDT leads to a strong neutrophilia (2–24 h), systemic increase of IL-6 (24 h), increased percentage of CD4+ and CD8+ T cells producing IFN-γ or CD69+ (2–24 h) and increased CD4+/CD8+ T cell ratio (2–24 h). At the tumour bed, T cell tumour infiltration disappeared after PDT but reappeared with a much higher incidence one day later. In addition, it is shown that the therapeutic effect of redaporfin-PDT is highly dependent on neutrophils and CD8+ T cells but not on CD4+ T cells. Full article
(This article belongs to the Special Issue The Past, Present and Future of Photodynamic Therapy for Cancers)
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Open AccessArticle
Design, Characterization, and Evaluation of scFvCD133/rGelonin: A CD133-Targeting Recombinant Immunotoxin for Use in Combination with Photochemical Internalization
J. Clin. Med. 2020, 9(1), 68; https://doi.org/10.3390/jcm9010068 - 26 Dec 2019
Cited by 5 | Viewed by 1071
Abstract
The objective of this study was to develop and explore a novel CD133-targeting immunotoxin (IT) for use in combination with the endosomal escape method photochemical internalization (PCI). scFvCD133/rGelonin was recombinantly constructed by fusing a gene (scFvCD133) encoding the scFv that targets both non-glycosylated [...] Read more.
The objective of this study was to develop and explore a novel CD133-targeting immunotoxin (IT) for use in combination with the endosomal escape method photochemical internalization (PCI). scFvCD133/rGelonin was recombinantly constructed by fusing a gene (scFvCD133) encoding the scFv that targets both non-glycosylated and glycosylated forms of both human and murine CD133/prominin-1 to a gene encoding the ribosome-inactivating protein (RIP) gelonin (rGelonin). RIP-activity was assessed in a cell-free translation assay. Selective binding and intracellular accumulation of scFvCD133/rGelonin was evaluated by flow cytometry and fluorescence microscopy. PCI of scFvCD133/rGelonin was explored in CD133high and CD133low cell lines and a CD133neg cell line, where cytotoxicity was evaluated by the MTT assay. scFvCD133/rGelonin exhibited superior binding to and a higher accumulation in CD133high cells compared to CD133low cells. No cytotoxic responses were detected in either CD133high or CD133low cells after 72 h incubation with <100 nM scFvCD133/rGelonin. Despite a severe loss in RIP-activity of scFvCD133/rGelonin compared to free rGelonin, PCI of scFvCD133/rGelonin induced log-fold reduction of viability compared to PCI of rGelonin. Strikingly, PCI of scFvCD133/rGelonin exceeded the cytotoxicity of PCI of rGelonin also in CD133low cells. In conclusion, PCI promotes strong cytotoxic activity of the per se non-toxic scFvCD133/rGelonin in both CD133high and CD133low cancer cells. Full article
(This article belongs to the Special Issue The Past, Present and Future of Photodynamic Therapy for Cancers)
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Open AccessArticle
Lipophilicity of Bacteriochlorin-Based Photosensitizers as a Determinant for PDT Optimization through the Modulation of the Inflammatory Mediators
J. Clin. Med. 2020, 9(1), 8; https://doi.org/10.3390/jcm9010008 - 19 Dec 2019
Cited by 9 | Viewed by 853
Abstract
Photodynamic therapy (PDT) augments the host antitumor immune response, but the role of the PDT effect on the tumor microenvironment in dependence on the type of photosensitizer and/or therapeutic protocols has not been clearly elucidated. We employed three bacteriochlorins (F2BOH, F [...] Read more.
Photodynamic therapy (PDT) augments the host antitumor immune response, but the role of the PDT effect on the tumor microenvironment in dependence on the type of photosensitizer and/or therapeutic protocols has not been clearly elucidated. We employed three bacteriochlorins (F2BOH, F2BMet and Cl2BHep) of different polarity that absorb near-infrared light (NIR) and generated a large amount of reactive oxygen species (ROS) to compare the PDT efficacy after various drug-to-light intervals: 15 min. (V-PDT), 3h (E-PDT) and 72h (C-PDT). We also performed the analysis of the molecular mechanisms of PDT crucial for the generation of the long-lasting antitumor immune response. PDT-induced damage affected the integrity of the host tissue and developed acute (protocol-dependent) local inflammation, which in turn led to the infiltration of neutrophils and macrophages. In order to further confirm this hypothesis, a number of proteins in the plasma of PDT-treated mice were identified. Among a wide range of cytokines (IL-6, IL-10, IL-13, IL-15, TNF-α, GM-CSF), chemokines (KC, MCP-1, MIP1α, MIP1β, MIP2) and growth factors (VEGF) released after PDT, an important role was assigned to IL-6. PDT protocols optimized for studied bacteriochlorins led to a significant increase in the survival rate of BALB/c mice bearing CT26 tumors, but each photosensitizer (PS) was more or less potent, depending on the applied DLI (15 min, 3 h or 72 h). Hydrophilic (F2BOH) and amphiphilic (F2BMet) PSs were equally effective in V-PDT (>80 cure rate). F2BMet was the most efficient in E-PDT (DLI = 3h), leading to a cure of 65 % of the animals. Finally, the most powerful PS in the C-PDT (DLI = 72 h) regimen turned out to be the most hydrophobic compound (Cl2BHep), allowing 100 % of treated animals to be cured at a light dose of only 45 J/cm2. Full article
(This article belongs to the Special Issue The Past, Present and Future of Photodynamic Therapy for Cancers)
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Open AccessArticle
Liposomal Lapatinib in Combination with Low-Dose Photodynamic Therapy for the Treatment of Glioma
J. Clin. Med. 2019, 8(12), 2214; https://doi.org/10.3390/jcm8122214 - 14 Dec 2019
Cited by 4 | Viewed by 962
Abstract
Background: Malignant gliomas are highly invasive and extremely difficult to treat tumours with poor prognosis and outcomes. Photodynamic therapy (PDT), mediated by Gleolan®, has been studied previously with partial success in treating these tumours and extending lifetime. We aim to determine whether combining [...] Read more.
Background: Malignant gliomas are highly invasive and extremely difficult to treat tumours with poor prognosis and outcomes. Photodynamic therapy (PDT), mediated by Gleolan®, has been studied previously with partial success in treating these tumours and extending lifetime. We aim to determine whether combining PDT using ALA-protoporphyrin IX (PpIX) with a liposomal formulation of the clinical epidermal growth factor receptor (EGFR) inhibitor, lapatinib, would increase the anti-tumour PDT efficacy. Methods: Lapatinib was given in vitro and in vivo 24 h prior to PDT and for 3–5 days following PDT to elicit whether the combination provided any benefits to PDT therapy. Live-cell imaging, in vitro PDT, and in vivo studies were performed to elucidate the effect lapatinib had on PDT for a variety of glioma cell lines and as well as GSC-30 neurospheres in vivo. Results: PDT combined with lapatinib led to a significant increase in PpIX accumulation, and reductions in the LD50 of PpIX mediated PDT in two EGFR-driven cell lines, U87 and U87vIII, tested (p < 0.05). PDT + lapatinib elicited stronger MRI-quantified glioma responses following PDT for two human glioma-derived tumours (U87 and GSC-30) in vivo (p < 0.05). Furthermore, PDT leads to enhanced survival in rats following treatment with lapatinib compared to lapatinib alone and PDT alone (p < 0.05). Conclusions: As lapatinib is approved for other oncological indications, a realization of its potential combination with PDT and in fluorescence-guided resection could be readily tested clinically. Furthermore, as its use would only be in acute settings, long-term resistance should not pose an issue as compared to its use as monotherapy. Full article
(This article belongs to the Special Issue The Past, Present and Future of Photodynamic Therapy for Cancers)
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Open AccessArticle
New Targeted Gold Nanorods for the Treatment of Glioblastoma by Photodynamic Therapy
J. Clin. Med. 2019, 8(12), 2205; https://doi.org/10.3390/jcm8122205 - 13 Dec 2019
Cited by 5 | Viewed by 1102
Abstract
This study describes the employment of gold nanorods (AuNRs), known for their good reputation in hyperthermia-based cancer therapy, in a hybrid combination of photosensitizers (PS) and peptides (PP). We report here, the design and the synthesis of this nanosystem and its application as [...] Read more.
This study describes the employment of gold nanorods (AuNRs), known for their good reputation in hyperthermia-based cancer therapy, in a hybrid combination of photosensitizers (PS) and peptides (PP). We report here, the design and the synthesis of this nanosystem and its application as a vehicle for the selective drug delivery and the efficient photodynamic therapy (PDT). AuNRs were functionalized by polyethylene glycol, phototoxic pyropheophorbide-a (Pyro) PS, and a “KDKPPR” peptide moiety to target neuropilin-1 receptor (NRP-1). The physicochemical characteristics of AuNRs, the synthesized peptide and the intermediate PP-PS conjugates were investigated. The photophysical properties of the hybrid AuNRs revealed that upon conjugation, the AuNRs acquired the characteristic properties of Pyro concerning the extension of the absorption profile and the capability to fluoresce (Φf = 0.3) and emit singlet oxygen (ΦΔ = 0.4) when excited at 412 nm. Even after being conjugated onto the surface of the AuNRs, the molecular affinity of “KDKPPR” for NRP-1 was preserved. Under irradiation at 652 nm, in vitro assays were conducted on glioblastoma U87 cells incubated with different PS concentrations of free Pyro, intermediate PP-PS conjugate and hybrid AuNRs. The AuNRs showed no cytotoxicity in the absence of light even at high PS concentrations. However, they efficiently decreased the cell viability by 67% under light exposure. This nanosystem possesses good efficiency in PDT and an expected potential effect in a combined photodynamic/photothermal therapy guided by NIR fluorescence imaging of the tumors due to the presence of both the hyperthermic agent, AuNRs, and the fluorescent active phototoxic PS. Full article
(This article belongs to the Special Issue The Past, Present and Future of Photodynamic Therapy for Cancers)
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Open AccessArticle
Effective Combined Photodynamic Therapy with Lipid Platinum Chloride Nanoparticles Therapies of Oral Squamous Carcinoma Tumor Inhibition
J. Clin. Med. 2019, 8(12), 2112; https://doi.org/10.3390/jcm8122112 - 02 Dec 2019
Cited by 2 | Viewed by 1556
Abstract
Encapsulating cisplatin (CDDP) into liposomes to form lipid-platinum-chloride nanoparticles (LPC NPs) has shown a promising anticancer effect in melanoma, bladder, and liver cancer models. This promising anticancer effect of LPC NPs challenges us to study its implications in combination with photodynamic therapy (PDT). [...] Read more.
Encapsulating cisplatin (CDDP) into liposomes to form lipid-platinum-chloride nanoparticles (LPC NPs) has shown a promising anticancer effect in melanoma, bladder, and liver cancer models. This promising anticancer effect of LPC NPs challenges us to study its implications in combination with photodynamic therapy (PDT). Herein, we report the therapeutic efficacy of PDT+LPC on a xenograft model of oral squamous cell carcinoma (OSCC). Results showed that PDT+LPC significantly reduced the tumor volume by up to ~112%. Meanwhile, LPC, PDT+CDDP, or the CDDP group showed ~98.8%, ~73.1%, or ~39.5% volume reductions, respectively. Histological examination suggests that PDT+LPC or LPC treatment showed minimal side effects on renal damage compared to either CDDP or the PDT+CDDP group. Immunohistochemistry staining (IHC) staining on Ki-67, CD31, cleaved caspase-3, TUNEL assays, and western blots of tumor suppressor p53 confirmed consistent results. Most importantly, PDT+LPC prolonged tumor growth inhibition, which leads to minimum chemotherapy treatment administrations. Results suggest that PDT cytotoxicity provided a potent additive effect towards chemotherapy efficacy. Therefore, combined PDT with LPC NPs enhanced the therapeutic outcome in human OSCC. Full article
(This article belongs to the Special Issue The Past, Present and Future of Photodynamic Therapy for Cancers)
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Open AccessArticle
Patient-Derived Head and Neck Cancer Organoids Recapitulate EGFR Expression Levels of Respective Tissues and Are Responsive to EGFR-Targeted Photodynamic Therapy
J. Clin. Med. 2019, 8(11), 1880; https://doi.org/10.3390/jcm8111880 - 05 Nov 2019
Cited by 17 | Viewed by 1702
Abstract
Patients diagnosed with head and neck squamous cell carcinoma (HNSCC) are currently treated with surgery and/or radio- and chemotherapy. Despite these therapeutic interventions, 40% of patients relapse, urging the need for more effective therapies. In photodynamic therapy (PDT), a light-activated photosensitizer produces reactive [...] Read more.
Patients diagnosed with head and neck squamous cell carcinoma (HNSCC) are currently treated with surgery and/or radio- and chemotherapy. Despite these therapeutic interventions, 40% of patients relapse, urging the need for more effective therapies. In photodynamic therapy (PDT), a light-activated photosensitizer produces reactive oxygen species that ultimately lead to cell death. Targeted PDT, using a photosensitizer conjugated to tumor-targeting molecules, has been explored as a more selective cancer therapy. Organoids are self-organizing three-dimensional structures that can be grown from both normal and tumor patient-material and have recently shown translational potential. Here, we explore the potential of a recently described HNSCC–organoid model to evaluate Epidermal Growth Factor Receptor (EGFR)-targeted PDT, through either antibody- or nanobody-photosensitizer conjugates. We find that EGFR expression levels differ between organoids derived from different donors, and recapitulate EGFR expression levels of patient material. EGFR expression levels were found to correlate with the response to EGFR-targeted PDT. Importantly, organoids grown from surrounding normal tissues showed lower EGFR expression levels than their tumor counterparts, and were not affected by the treatment. In general, nanobody-targeted PDT was more effective than antibody-targeted PDT. Taken together, patient-derived HNSCC organoids are a useful 3D model for testing in vitro targeted PDT. Full article
(This article belongs to the Special Issue The Past, Present and Future of Photodynamic Therapy for Cancers)
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Open AccessArticle
Stroma-Rich Co-Culture Multicellular Tumor Spheroids as a Tool for Photoactive Drugs Screening
J. Clin. Med. 2019, 8(10), 1686; https://doi.org/10.3390/jcm8101686 - 15 Oct 2019
Cited by 12 | Viewed by 1376
Abstract
Conventional 3D multicellular tumor spheroids of head and neck squamous cell carcinoma (HNSCC) consisting exclusively of cancer cells have some limitations. They are compact cell aggregates that do not interact with their extracellular milieu, thus suffering from both insufficient extracellular matrix (ECM) deposition [...] Read more.
Conventional 3D multicellular tumor spheroids of head and neck squamous cell carcinoma (HNSCC) consisting exclusively of cancer cells have some limitations. They are compact cell aggregates that do not interact with their extracellular milieu, thus suffering from both insufficient extracellular matrix (ECM) deposition and absence of different types of stromal cells. In order to better mimic in vivo HNSCC tumor microenvironment, we have constructed a 3D stroma-rich in vitro model of HNSCC, using cancer-associated MeWo skin fibroblasts and FaDu pharynx squamous cell carcinoma. The expression of stromal components in heterospheroids was confirmed by immunochemical staining. The generated co-culture FaDu/MeWo spheroids were applied to study penetration, distribution and antitumor efficacy of photoactive drugs such as Temoporfin and Chlorin e6 used in the photodynamic therapy flow cytometry and fluorescence microscopy techniques. We also investigated the distribution of photodiagnostic agent Indocyanine Green. We demonstrated that the presence of stroma influences the behavior of photoactive drugs in different ways: (i) No effect on Indocyanine Green distribution; (ii) lower accumulation of Chlorin e6; (iii) better penetration and PDT efficiency of Temoporfin. Overall, the developed stroma-rich spheroids enlarge the arsenal of in vitro pre-clinical models for high-throughput screening of anti-cancer drugs. Full article
(This article belongs to the Special Issue The Past, Present and Future of Photodynamic Therapy for Cancers)
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Open AccessArticle
Tracking Photodynamic- and Chemotherapy-Induced Redox-State Perturbations in 3D Culture Models of Pancreatic Cancer: A Tool for Identifying Therapy-Induced Metabolic Changes
J. Clin. Med. 2019, 8(9), 1399; https://doi.org/10.3390/jcm8091399 - 06 Sep 2019
Cited by 5 | Viewed by 1007
Abstract
The metabolic plasticity of cancer cells is considered a highly advantageous phenotype that is crucial for disease progression and acquisition of treatment resistance. A better understanding of cancer metabolism and its adaptability after treatments is vital to develop more effective therapies. To screen [...] Read more.
The metabolic plasticity of cancer cells is considered a highly advantageous phenotype that is crucial for disease progression and acquisition of treatment resistance. A better understanding of cancer metabolism and its adaptability after treatments is vital to develop more effective therapies. To screen novel therapies and combination regimens, three-dimensional (3D) culture models of cancers are attractive platforms as they recapitulate key features of cancer. By applying non-perturbative intensity-based redox imaging combined with high-throughput image analysis, we demonstrated metabolic heterogeneity in various 3D culture models of pancreatic cancer. Photodynamic therapy and oxaliplatin chemotherapy, two cancer treatments with relevance to pancreatic cancer, induced perturbations in redox state in 3D microtumor cultures of pancreatic cancer. In an orthotopic mouse model of pancreatic cancer, a similar disruption in redox homeostasis was observed on ex vivo slices following photodynamic therapy in vivo. Taken together, redox imaging on cancer tissues combined with high-throughput analysis can elucidate dynamic spatiotemporal changes in metabolism following treatment, which will benefit the design of new metabolism-targeted therapeutic approaches. Full article
(This article belongs to the Special Issue The Past, Present and Future of Photodynamic Therapy for Cancers)
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Open AccessArticle
Systematic Evaluation of Light-Activatable Biohybrids for Anti-Glioma Photodynamic Therapy
J. Clin. Med. 2019, 8(9), 1269; https://doi.org/10.3390/jcm8091269 - 21 Aug 2019
Cited by 9 | Viewed by 1250
Abstract
Photosensitizing biomolecules (PSBM) represent a new generation of light-absorbing compounds with improved optical and physicochemical properties for biomedical applications. Despite numerous advances in lipid-, polymer-, and protein-based PSBMs, their effective use requires a fundamental understanding of how macromolecular structure influences the physicochemical and [...] Read more.
Photosensitizing biomolecules (PSBM) represent a new generation of light-absorbing compounds with improved optical and physicochemical properties for biomedical applications. Despite numerous advances in lipid-, polymer-, and protein-based PSBMs, their effective use requires a fundamental understanding of how macromolecular structure influences the physicochemical and biological properties of the photosensitizer. Here, we prepared and characterized three well-defined PSBMs based on a clinically used photosensitizer, benzoporphyrin derivative (BPD). The PSBMs include 16:0 lysophosphocholine-BPD (16:0 Lyso PC-BPD), distearoyl-phosphoethanolamine-polyethylene-glycol-BPD (DSPE-PEG-BPD), and anti-EGFR cetuximab-BPD (Cet-BPD). In two glioma cell lines, DSPE-PEG-BPD exhibited the highest singlet oxygen yield but was the least phototoxic due to low cellular uptake. The 16:0 Lyso PC-BPD was most efficient in promoting cellular uptake but redirected BPD’s subcellular localization from mitochondria to lysosomes. At 24 h after incubation, proteolyzed Cet-BPD was localized to mitochondria and effectively disrupted the mitochondrial membrane potential upon light activation. Our results revealed the variable trafficking and end effects of PSBMs, providing valuable insights into methods of PSBM evaluation, as well as strategies to select PSBMs based on subcellular targets and cytotoxic mechanisms. We demonstrated that biologically informed combinations of PSBMs to target lysosomes and mitochondria, concurrently, may lead to enhanced therapeutic effects against gliomas. Full article
(This article belongs to the Special Issue The Past, Present and Future of Photodynamic Therapy for Cancers)
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Review

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Open AccessReview
Photochemical Internalization for Intracellular Drug Delivery. From Basic Mechanisms to Clinical Research
J. Clin. Med. 2020, 9(2), 528; https://doi.org/10.3390/jcm9020528 - 14 Feb 2020
Cited by 13 | Viewed by 1504
Abstract
Photochemical internalisation (PCI) is a unique intervention which involves the release of endocytosed macromolecules into the cytoplasmic matrix. PCI is based on the use of photosensitizers placed in endocytic vesicles that, following light activation, lead to rupture of the endocytic vesicles and the [...] Read more.
Photochemical internalisation (PCI) is a unique intervention which involves the release of endocytosed macromolecules into the cytoplasmic matrix. PCI is based on the use of photosensitizers placed in endocytic vesicles that, following light activation, lead to rupture of the endocytic vesicles and the release of the macromolecules into the cytoplasmic matrix. This technology has been shown to improve the biological activity of a number of macromolecules that do not readily penetrate the plasma membrane, including type I ribosome-inactivating proteins (RIPs), gene-encoding plasmids, adenovirus and oligonucleotides and certain chemotherapeutics, such as bleomycin. This new intervention has also been found appealing for intracellular delivery of drugs incorporated into nanocarriers and for cancer vaccination. PCI is currently being evaluated in clinical trials. Data from the first-in-human phase I clinical trial as well as an update on the development of the PCI technology towards clinical practice is presented here. Full article
(This article belongs to the Special Issue The Past, Present and Future of Photodynamic Therapy for Cancers)
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Open AccessReview
Preclinical and Clinical Evidence of Immune Responses Triggered in Oncologic Photodynamic Therapy: Clinical Recommendations
J. Clin. Med. 2020, 9(2), 333; https://doi.org/10.3390/jcm9020333 - 24 Jan 2020
Cited by 11 | Viewed by 1096
Abstract
Photodynamic therapy (PDT) is an anticancer strategy utilizing light-mediated activation of a photosensitizer (PS) which has accumulated in tumor and/or surrounding vasculature. Upon activation, the PS mediates tumor destruction through the generation of reactive oxygen species and tumor-associated vasculature damage, generally resulting in [...] Read more.
Photodynamic therapy (PDT) is an anticancer strategy utilizing light-mediated activation of a photosensitizer (PS) which has accumulated in tumor and/or surrounding vasculature. Upon activation, the PS mediates tumor destruction through the generation of reactive oxygen species and tumor-associated vasculature damage, generally resulting in high tumor cure rates. In addition, a PDT-induced immune response against the tumor has been documented in several studies. However, some contradictory results have been reported as well. With the aim of improving the understanding and awareness of the immunological events triggered by PDT, this review focuses on the immunological effects post-PDT, described in preclinical and clinical studies. The reviewed preclinical evidence indicates that PDT is able to elicit a local inflammatory response in the treated site, which can develop into systemic antitumor immunity, providing long-term tumor growth control. Nevertheless, this aspect of PDT has barely been explored in clinical studies. It is clear that further understanding of these events can impact the design of more potent PDT treatments. Based on the available preclinical knowledge, recommendations are given to guide future clinical research to gain valuable information on the immune response induced by PDT. Such insights directly obtained from cancer patients can only improve the success of PDT treatment, either alone or in combination with immunomodulatory approaches. Full article
(This article belongs to the Special Issue The Past, Present and Future of Photodynamic Therapy for Cancers)
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Open AccessReview
Development of Prodrugs for PDT-Based Combination Therapy Using a Singlet-Oxygen-Sensitive Linker and Quantitative Systems Pharmacology
J. Clin. Med. 2019, 8(12), 2198; https://doi.org/10.3390/jcm8122198 - 13 Dec 2019
Cited by 2 | Viewed by 1090
Abstract
Photodynamic therapy (PDT) has become an effective treatment for certain types of solid tumors. The combination of PDT with other therapies has been extensively investigated in recent years to improve its effectiveness and expand its applications. This focused review summarizes the development of [...] Read more.
Photodynamic therapy (PDT) has become an effective treatment for certain types of solid tumors. The combination of PDT with other therapies has been extensively investigated in recent years to improve its effectiveness and expand its applications. This focused review summarizes the development of a prodrug system in which anticancer drugs are activated locally at tumor sites during PDT treatment. The development of a singlet-oxygen-sensitive linker that can be conveniently conjugated to various drugs and efficiently cleaved to release intact drugs is recapitulated. The initial design of prodrugs, preliminary efficacy evaluation, pharmacokinetics study, and optimization using quantitative systems pharmacology is discussed. Current treatment optimization in animal models using physiologically based a pharmacokinetic (PBPK) modeling approach is also explored. Full article
(This article belongs to the Special Issue The Past, Present and Future of Photodynamic Therapy for Cancers)
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Open AccessReview
Photodynamic Therapy: A Brief History
J. Clin. Med. 2019, 8(10), 1581; https://doi.org/10.3390/jcm8101581 - 02 Oct 2019
Cited by 25 | Viewed by 1467
Abstract
Photodynamic therapy (PDT) involves the selective sensitization of tissues to light. A major advance in the field occurred when Thomas Dougherty at the Roswell Park Cancer Institute initiated a series of clinical studies that eventually led to FDA approval of the procedure. This [...] Read more.
Photodynamic therapy (PDT) involves the selective sensitization of tissues to light. A major advance in the field occurred when Thomas Dougherty at the Roswell Park Cancer Institute initiated a series of clinical studies that eventually led to FDA approval of the procedure. This report contains a summary of Dougherty’s contributions and an assessment of where this has led, along with a summary of implications for future drug development. Full article
(This article belongs to the Special Issue The Past, Present and Future of Photodynamic Therapy for Cancers)
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